Alzheimer's disease (AD) is a neurodegenerative syndrome generally linked with ageing which leads patients to a progressive deterioration of their cognitive and behavioural functions. The great majority of cases of AD has causes that are currently substantially unknown. Also for this reason, today there are still no therapeutic treatments able to halt the progression of the disease, even though some drugs have recently been put on the market, aimed especially at the control of the cognitive symptoms. These drugs—Tacrine (Cognex®), Donepezil (Aricept®) and Rivastigmine (Exelon®)—share the same action mechanism, which consists of the inhibition of acetylcholinesterase (AChE).
The therapeutic approach based on the inhibition of AChe is founded on the observation that the neuron degeneration associated with AD occurs prevalently in cerebral areas innervated by cholinergic neurons. The loss of cholinergic activity in those areas (cortex and hippocampus, especially) would be responsible for the cognitive dysfunctions typical of AD. AChe is the enzyme that inactivates the cholinergic neurotransmitter acetylcholine (ACh), and the hypothesis has been expressed that the block of the functioning of this enzyme could prolong the stimulation of the receptor, strengthening cholinergic transmission. The known drugs mentioned above derive from the application of this hypothesis called “cholinergic hypothesis” (Bartus, R. T.; Dean, R. L., 3rd; Beer, B.; Lippa, A. S. The cholinergic hypothesis of geriatric memory dysfunction. Science 1982, Vol. 217, p. 408-414). However, one cannot overlook the limits of this approach which consist substantially in the lack of action on the progression of the disease and in the presence of undesired collateral effects, which limit dosage and can induce the patient to interrupt taking one of the drugs mentioned above.
Although the strengthening of cholinergic transmission through the inhibition of AchE is a useful approach to the treatment of cognitive symptoms associated with AD, it has recently been proposed that the loss of neurons and the consequent appearance of cognitive symptoms are the result of a cascade of biochemical events linked with the overproduction of β-amyloid protein in certain cerebral areas. This protein tends to aggregate, forming extracellular deposits, which give rise to the typical lesions found in the brain of AD patients: senile plaques. The presence of these plaques produces responses of an inflammatory and oxidative type in the surrounding tissue, triggering a chain of toxic events, including an increase of the phosphorylation of tau protein, due to the activation of enzymes of inflammation and to the formation of oxygenated radical species. The progression of neurodegeneration derives from the impossibility of controlling the spread of these harmful effects. It is therefore necessary to discover pharmacological instruments that are able to act as far upstream as possible in the neurodegenerative cascade. Moreover, it is important to stress that there are other pathologies besides Alzheimer's disease characterised by deposits of Aβ. These pathologies include: Down's syndrome, hereditary cerebral haemorrhage associated with amyloidosis of the “Dutch type”, amyloidosis associated with chronic inflammations, amyloidosis associated with multiple myelomas and other dyscrasias of the B lymphoid haematic cells, amyloidosis associated with diabetes type II, amyloidosis associated with diseases deriving from pryons such as Creutzfeldt-Jakob's disease, the Gertsmann-Straussler syndrome, Kuru and scrapie in sheep (WO 02/00603).
From the above it is clear that there is still a considerable need to make medicaments available for the treatment of AD and for the treatment of pathologies characterised by deposits of Aβ.